Project Summary/Abstract: Over one million Americans suffer from Systemic Lupus Erythematosus, an autoimmune disease for which there is no cure. Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease. The disease presentation is heterogenous, women are nine times more likely to develop SLE than men, and lupus is significantly more prevalent in people of Asian, Hispanic, Native American, and African ancestry than people of European ancestry. Lupus is a significantly understudied disease. Monozygotic twin concordance is found to be as low as 25% and familial aggregation studies suggest that lupus results at least in part from genetic predisposition. Most experts in the field agree that gene-environment interactions are important for lupus development. Recent work from our laboratory suggests that aberrant DNA repair leads to the development of lupus in a mouse model of the disease. We originally showed that a mutation in the POLB gene in mice results in development of lupus as a result of defective VDJ recombination and somatic hypermutation. In collaboration with Dr. Lindsey Criswell we have now identified a large number of coding germline variants that are enriched in individuals with lupus. In preliminary research, we have demonstrated that mice harboring one of these variants within the mismatch repair pathway develop high levels of antinuclear antibodies and lupus-associated lung disease. We have shown that somatic hypermutation is abnormal in these mice and results in the production of autoantibodies. Our RIVER project is focused on providing mechanistic insights into the development of lupus as a result of gene-environment interactions. A challenge in the field is understanding how environmental exposures influence lupus development. We suggest that many previous analyses may be underpowered because the genetic predisposition factors of the individuals studied are likely to differ, and that genetic factors play a significant role in the response of the organism to the environment. Our approach to address this challenge is to construct mouse models of coding genetic variants in DNA repair genes that are significantly enriched in individuals with lupus. This will be followed by characterization of the disease pathologies emerging in these mice in the absence and presence of environmental exposures that are known to be linked to lupus development. We will then take a combined genetic, molecular, and biochemical approach to elucidate underlying mechanistic insights into the development of lupus. Our project has significant potential to uncover the genetic and environmental bases of lupus development and to yield paradigm-shifting results that will impact the treatment of this devastating disease.